The development of cancer involves the inactivation of specific genes involved in growth regulation. Recent work from our laboratory and others have identified two tumor suppressor genes that belong to the Protein 4.1 family of molecules (the NF2 gene product, merlin, and Protein 4.1B) and are deleted in brain, breast, and lung cancers. In specific brain tumors (meningiomas), Protein 4.1B expression is lost early in tumor development and may represent an initiating event in brain tumorigenesis. We have previously shown that (a) Protein 4.1B suppresses meningioma cell growth in vitro, (b) Protein 4.1B associates with both CD44 and 14-3-3, and (c) the minimal growth suppressor domain of Protein 4.1 B maps to a region that mediates binding to both CD44 and 14-3-3. In this proposal, I plan to test the hypothesis that the ability of Protein 4.1B to suppress meningioma cell growth requires regulated interactions with both CD44 and 14-3-3. Specifically, I wish to (1) identify and characterize the minimal domain of Protein 4.1B required for growth suppression, (2) define the molecular determinants within the Protein 4.1B growth suppressor domain that mediate interactions with CD44 and 14-3-3, and (3) determine whether the binding of Protein 4.1B to CD44 and 14-3-3 is critical for Protein 4.1B growth suppression. These studies are focused on elucidating the mechanism(s) underlying tumor suppression of one of the critical growth regulators important in brain tumor formation.